VITAMIN D. Hilft es dem Intensivpatienten?

Transkript

1 Karin Amrein, MD, MSc Assoziierte Professorin Medical University of Graz, Austria Division of Endocrinology and Metabolism VITAMIN D Hilft es dem Intensivpatienten?

2 CONFLICTS OF INTEREST BBraun Fresenius Kabi MSD Novartis Novo Nordisk Nycomed Aguettant Sinapharm

3 VDR KNOCKOUT (KO) MAUS Bouillon R et al. Endocrine Reviews 2008; 29: Keisala et al. Premature aging in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol Jul;115(3-5):91-7

4 NICHT KLASSISCHE WIRKUNG KLASSISCHE WIRKUNG HD

5 BASICS VITAMIN D VITAMIN D IST EIN STEROIDHORMON (VDR!) VITAMIN D REGULIERT ~ 200 GENE CALCITRIOL (AKTIVES VITAMIN D) WIRD NICHT NUR IN DER NIERE PRODUZIERT VITAMIN D HAT NEBEN DER KALZIUMHOMÖOSTASE VIELE ANDERE FUNKTIONEN

6 BASICS VITAMIN D BEI KRITISCH KRANKEN (ERWACHSENE UND KINDER) EIN VITAMIN D MANGEL IST HÄUFIG MIT SCHLECHTEM OUTCOME ASSOZIIERT (MORTALITÄT, NIERENVERSAGEN, SEPSIS ) FRAGE: IST VITAMIN D NUR EIN MARKER ODER MEHR?

7 DEFINITION Defizienz < 20ng/ml <50nmol/L Insuffizienz 20-30ng/ml 50-75nmol/L Normal >30ng/ml >75nmol/L Intoxikation > 150 ng/ml > 375nmol/L Holick M., NEJM 2007

8 MECHANISMEN VON VITAMIN D - ICU Allgemein- Bevölkerung Kritisch Kranke Infektionen Lunge/Muskel Herz Atemwegsinfekte, Tuberkulose COPD, Myopathie, Myalgia Herzinfarkt, Herzinsuffizienz, Sudden Cardiac Death Nosokomiale Infekte Sepsis, SIRS Lungenversagen Prolong. Weaning, Critical Illness Myopathy Kardiogener Schock, Arrhythmie Adaptiert von: Lee P. et al., Intensive Care Med Dec;35(12):

9 Vitamin D Council Podcast 03: Vitamin D in hospitalized patients Intensive Care Network

10 Correction of Vitamin D Deficiency in Critically Ill Patients ClinicalTrials: NCT Setting Intervention Primärer Endpunkt Sekundäre Endpunkte randomisiert, doppelblind, placebokontrolliert 5 ICUs (Neuro, Med, Chirurgie 3x) 480 Pat. > 48 Std. auf ICU; 25(OH)D 20 ng/ml 540,000 IU Vitamin D3 vs. Placebo 1x po/ngs 90,000 IU/ Monat vs. Placebo 5x Aufenthaltsdauer im Spital Mortalität, Aufenthaltsdauer auf ICU, Labor, 6- Monats-Follow Up Amrein BMC Disorders 2012, JAMA 2014

11 RECOMMENDED DAILY INTAKE & UPPER LIMIT IOM (ALLGEMEINBEVÖLKERUNG!)

12 Correction of Vitamin D Deficiency in Critically Ill Patients ClinicalTrials: NCT Setting Intervention Primärer Endpunkt Sekundäre Endpunkte randomisiert, doppelblind, placebokontrolliert 5 ICUs (Neuro, Med, Chirurgie 3x) 480 Pat. > 48 Std. auf ICU; 25(OH)D 20 ng/ml 540,000 IU Vitamin D3 vs. Placebo 1x po/ngs 90,000 IU/ Monat vs. Placebo 5x Aufenthaltsdauer im Spital Mortalität, Aufenthaltsdauer auf ICU, Labor, 6- Monats-Follow Up Amrein BMC Disorders 2012, JAMA 2014

13 RESULTATE PRIMÄRER ENDPUNKT SPITALAUFENTHALT (Tage) Vitamin D3: 20.1 [IQR ] Placebo: 19.3 [IQR ] P=0.981

14 RESULTATE SEKUNDÄRER ENDPUNKT % PATIENTEN MIT >30 NG/ML TAG 7 52% = KORREKTUR DES VITAMIN D - MANGELS

15 RESULTATE SEKUNDÄRER ENDPUNKT SUBGRUPPE 12NG/ML (n=200; 42%) SPITALSSTERBLICHKEIT Vitamin D3: 28.6% Placebo: 46.1% HR 0.56 [95%CI ] P=0.01 (log rank), 0.04 (for interaction)

16 RESULTATE SEKUNDÄRER ENDPUNKT SUBGRUPPE 12NG/ML (n=200; 42%) SPITALSSTERBLICHKEIT Vitamin D3: 28.6% Placebo: 46.1% HR 0.56 [95%CI ] P=0.01 (log rank), 0.04 (for interaction)

17 6 month mortality rate 42.9 vs. 35.0% P=0.087

18 6 month mortality rate 37.5 vs. 35.3%

19 6 month mortality rate 50.0 vs. 34.7%

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21 VITAMIN D & MORTALITÄT

22 MENDELIAN RANDOMIZATION 96,000 Dänen, Copenhagen - Primary endpoint: overall mortality, cancer mortality and other mortalities. - genes associated with 25(OH)D levels <8 ng/ml (<20 nmol/l) caused a 30% higher mortality risk and a 40% higher risk of cancer deathsm no correlation with cardiovascular death. - Genetic variants in DHCR7,CYP2R1!? Afzal, S.; Brøndum-Jacobsen, P.; Bojesen, S.E.; Nordestgaard, B.G. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ 2014

23 COCHRANE META-ANALYSE 2011 Bjelakovic 2011

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25 COCHRANE META-ANALYSE 2014 Main results We identified 159 trials, 56 randomised trials with 95,286 participants provided usable data on mortality. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/ml). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/ml).... only vitamin D3 decreased mortality: RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I2 = 0%; 75,927 participants; 38 trials). Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials). Bjelakovic 2014

26 VITAMIN D & SUDDEN CARDIAC DEATH Follow-up 7.7 Years 760 Deaths (188 Sudden Cardiac Deaths) 25(OH)D levels >30 ng/ml ng/ml ng/ml HR: 5.05 ( ) Severely deficient vs. normal <10 ng/ml Pilz S, et al. J Clin Endocrinol Metab 2008; 93:

27 VITAMIN D AND HOSPITAL MORTALITY

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29 JCEM 2012

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31 MORTALITY Autier 2013

32 Bolland 2014

33 Heaney 2013

34 WELCHE INTERVENTIONEN HABEN JEMALS IM MULTICENTER DESIGN DIE MORTALITÄT REDUZIERT? Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect*. Landoni, Giovanni et al., Critical Care Medicine. 43(8): , August 2015.

35 HELFEN ANTIBIOTIKA INTENSIVPATIENTEN? JA!?!!! ABER NUR WENN EINE INFEKTION VORLIEGT

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37 LARGE ONGOING RCT s VITAL Study: 25,000 pat > 50/55 yrs, US, FIND Study 18,000 pat, Finland Vida Study: > 5,000 elderly pat., NZ DO HEALTH Study: 2152 pat. > 70; 7 europ. Centers

38 LEITLINIEN ZIEL 25(OH)D > 20ng/ml IOM (ALLGEMEINBEVÖLKERUNG) IU/d, max IU/d ENDOCRINE SOCIETY (RISIKOPAT.) IU PRO TAG!!! SICHERES LIMIT 10,000 IU/d Ross 2011 Holick 2011

39 CONCLUSIO ZIELSPIEGEL > 20 ng/ml (zumindest Knochen) ERFORDERLICHE DOSIS oft 2000 IU/d oder mehr LINK VITAMIN D UND ICU - Outcome VITdAL-ICU: Signifikant niedrigere Spitalssterblichkeit bei prädefinierter Subgruppe mit schwerem Vitamin D Mangel (NNT 6; absolute Differenz 17.5%, relative 44%)

40 KNOCHEN RELEVANT? HUMERUS FRAKTUR SCHENKEL HALSFRAKTUR

41 FRAGILITY FRACTURES (fx) Fragility fx are associated with increased morbidity Increased mortality One year after hip fx Institutionalization and death is a major problem (up to 50%!) Pasco 2005, Edwards 2009, Papaioannou 2010

42 FRACTURES AFTER ICU? MEN: 2.41 fx per 100 patient years WOMEN: 3.84 fx per 100 patient years 65% increased risk compared with agematched random population sample (HR 1.65, 95% , p=0.02, elderly women) Orford CCM 2011

43 DANKE!

44 SIX-MONTH FOLLOW UP (etable 5) 17 deaths less n=80 personal follow up Prespecified Subgroup Population Severe Vitamin D Deficiency a Less Severe Vitamin D Deficiency b Placebo Vitamin D3 Placebo Vitamin D3 P-value (n=51) (n=64) (n=85) (n=89) P-value Number of readmissions 20 (39.2%) 24 (37.5%) (45.9%) 31 (34.8%) 0.14 No. of pat with respiratory tract infections 8 (15.7%) 6 (9.4%) (9.4%) 3 (3.4%) 0.13 Quality of life (SF-12), points Physical Mental Hand grip strength, mmhg Left Right Falls (no. of pat) Fractures (no. of pat) Timed up & go test, seconds BMD, T-Score 37.6± ± ± ± ± ± ± ± (n=13) (n=13) (n=27) (n=23) 81.9± ± ± ± ± ± ± ± (27.5%) 16 (25.0%) (22.4%) 11 (12.4%) (2.0%) 1 (1.6%) - 1 (1.2%) 1 (1.1%) - (n=13) (n=13) (n=27) (n=22) (6-15) 11 (5-90) 9 (4-17) 8.5 (6-14) (n=13-14) (n=14) (n=25-26) (n=22-23) lumbar spine -0.22± ± ± ± femoral neck ± ± ± ±

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